There is a wide variation in the frequency of exacerbations among patients with COPD. Factors that determine the frequency of exacerbations are poorly understood. The human lung has a complex, multifaceted, innate defense system that represents the first line of defense against environmental agents, infectious or otherwise, that are capable of causing exacerbations. We hypothesize that disruption of the innate lung defense allows environmental agents capable of causing exacerbations to establish themselves in the tracheobronchial tree and induce exacerbations. Furthermore, the level of disruption of one or more components of the innate lung defense determines the frequency of exacerbations in COPD. Patients (n=320) with stable COPD will be enrolled, various components of innate lung defense will be assessed and correlated with the number of exacerbations experienced over the next 12 months. In Specific Aim 1 whether impairment of mucociliary clearance is associated with frequency of exacerbations will be established. In Specific Aim 2 sputum and bronchoalveolar lavage concentrations of airway antimicrobial polypeptides, specifically lysozyme, lactoferrin, secretory leucocyte protease inhibitor (SLPI) and surfactant proteins A (SP-A) and D (SP-D) will be determined and their impact on frequency of exacerbations determined. In Specific Aim 3 fundamental immunologic mechanisms regulated by alveolar macrophages that contribute to frequency of exacerbations of COPD will be identified. Specifically, the role and mechanisms of impaired phagocytosis by alveolar macrophages of respiratory pathogens that contribute to COPD exacerbations will be determined. .In addition, innate immunoregulatory properties of alveolar macrophages that contribute to COPD exacerbations will be determined. In Specific Aim 4 the relationship between the interaction of airway epithelial cells with bacterial pathogens and frequency of exacerbations will be explored. Specifically, bacterial adherence and immunologic response of airway epithelial cells to bacterial pathogens will be examined. The overall goal of this research is to identify specific aspects of the innate defense of the lung that determine the frequency of exacerbations in COPD that will serve as potential therapeutic targets to reduce exacerbations.